Project Summary/Abstract Rehabilitation interventions such as physical training and neural stimulation after spinal cord injury (SCI) have been shown to reorganize motor pathways in the brain, the route to spinal cord (aka corticospinal tract), and at the spinal level to improve lost functional movements. This process is called neural plasticity. However, both physical training and neural stimulation require a large number of repetitions, and the retention of the intervention effects may be fleeting. Therefore, an important need remains to find a method to couple with rehabilitation interventions to promote longer-lasting neural plasticity. In this proposal we will test Remote ischemic conditioning (RIC), which has been shown to promote neural plasticity and has practical and theoretical advantages. RIC consists of transiently restricting blood flow to any `remote' limb using a blood pressure cuff. This induces several of the body's systemic defensive reactions. RIC's original intended use was to reduce myocardial infarction size through systemic cardioprotective effects. More recently, RIC was shown to improve motor learning, indicating that RIC may promote systemic neural plasticity. However, the mechanism of enhancing neural plasticity induced by RIC is still not clear. We propose that RIC alters motor pathway excitability within the brain, corticospinal tract or spinal cord through a combination of systemic increases in plasticity-promoting factors and inhibition of inflammatory factors. We have designed a clinical trial to test our hypothesis in 8 persons with SCI and 8 able-bodied controls. All participants will receive active/sham RIC plus a hand exercise. We will measure motor neuron excitability in the pathway from the brain to spinal cord before and after RIC as well as after hand exercise. This is the first study of RIC in an SCI population. We will therefore monitor the heart rate (HR), blood pressure (BP) and oxygen saturation (SaO2) change and autonomic nervous system (ANS) responses during RIC. Aim 1 will measure the change of motor neuron excitability from the brain to the spinal cord after active RIC + training versus sham RIC + training in persons with cervical SCI and able-bodied controls. Aim 2 will measure the changes of inflammatory mediator gene expression from participants' blood sample before/after RIC. Aim 3 will monitor the changes of HR, BP and SaO2 during RIC and measure the responses of ANS via heart rate variability. Outcomes from this proposed study will provide the preliminary data to design larger studies of RIC combined with long-term rehabilitation interventions, and even pairing RIC with more advanced intervention such as robotic training or neural stimulation.